Field of the Invention
The present invention relates to the field of compounds for the treatment and/or prevention of neurodegenerative diseases.
Related Art
Presented below is background information on certain aspects of the present invention as they may relate to technical features referred to in the detailed description, but not necessarily described in detail. The discussion below should not be construed as an admission as to the relevance of the information to the claimed invention or the prior art effect of the material described.
Cell Division and Alzheimer's Disease (“AD”)
Reisberg US 2004/0127471, published Jul. 1, 2004, entitled “Methods of treating age associated memory impairment (AAMI), mild cognitive impairment (MCI), and dementias with cell cycle inhibitors,” discloses a number of mechanisms which are attributed to neurodegenerative diseases. Among these are the suggestion that tetracycline-based compounds, in addition to inhibiting neuronal cell cycle progression at either an early cell cycle phase or generally, either alone or in combination with one or more agents are capable of reducing mitogenic stimulation and offering neuroprotection to patients with neurodegenerative diseases.
Reisberg further suggests that normal cell division occurs through a molecular biologic process known as the cell cycle. The cell cycle consists of major phases known as the G 1 phase, the S phase, the G 2 phase, the M phase and the G 0 phase. These phases of cell division correspond to the early growth phase, the synthesis phase, a later growth phase, a mitosis phase, and a resting phase. Progression through these phases is regulated by a series of enzymes, which include activators and inhibitors. However, this publication does not disclose that the compounds contemplated actually inhibit cell cycle progression.
Wang et al., “Minocycline inhibits caspase-independent and -dependent mitochondrial cell death pathways in models of Huntington's disease,” Proc. Nat. Acad. Sci., 100(18) 10483-10487 (2003), report that minocycline is a drug that directly inhibits both caspase-independent and -dependent mitochondrial cell death pathways.
Yang et al., “Ectopic Cell Cycle Events Link Human Alzheimer's Disease and Amyloid Precursor Protein Transgenic Mouse Models,” The Journal of Neuroscience, Jan. 18, 2006, 26(3):775-784, disclose results which document the initiation of a cell-cycle process in the neurons of several mouse models of familial AD. There are a growing number of conditions in the mouse in which neuronal cell death is associated with re-entrance into a lethal cell cycle. The authors further state that several transgenic mouse models have been generated that recreate the genetic changes found in familial AD. Transgenic mice expressing mutant human amyloid precursor protein (APP) genes exhibit an age-related development of diffuse and neuritic plaques, with plaque burdens often approaching those found in advanced cases of AD. This has proven to be a valuable resource in the exploration and design of disease therapies. In addition, the AD mice show microglial activation, astrocytosis, and changes in neuronal cytoskeletal proteins including tau. Many of these model organisms have also been shown to have significant memory deficits. Despite these parallels to the human disease state, however, none of the mouse models has yet been shown to develop the typical neurofibrillary tangles. The reason for the discrepancy between the human and mouse neurodegenerative phenotype is unclear. However, there has been shown a close association between the neuronal cell death in AD and cellular processes that normally only occur during a mitotic cell cycle. Cell-cycle-related proteins are expressed in neurons that are “at risk” in AD but not in age-matched controls or in regions of the AD brain itself where degeneration is not prevalent. This ectopic re-expression of cell-cycle markers is functional as shown by fluorescent in situ hybridization (FISH).
Tetracycline Derivatives
A number of patents and publications disclose tetracycline derivatives and methods of their preparation, such as, U.S. Pat. No. 7,056,902, entitled “4-dedimethylamino tetracycline compounds”, issued Jun. 6, 2006; U.S. Pat. No. 7,094,806, entitled “7, 8 and 9-substituted tetracycline compounds,” issued Aug. 22, 2006; U.S. Pat. No. 7,202,235, entitled “Tetracycline compounds for treatment of cryptosporidium parvum related disorders,” issued Apr. 10, 2007; and U.S. Pat. No. 7,208,482, entitled “9-aminoacyl tetracycline compounds and methods of use thereof,” issued Apr. 24, 2007. EP20020748169, by Levy, et al., published Apr. 1, 2004, entitled, “Tetracycline compounds having target therapeutic activities,” discloses various synthetic routes to tetracycline derivatives. US 2007/0093455 to Abato et al., entitled “10-Substituted Tetracyclines and Methods of use thereof,” published Apr. 26, 2007, purports to disclose compounds with 9-10 rings, e.g., at page 9. Exemplary compound Q showed superior inhibition of bacteria.
Use of Minocycline
US 20030092683 by Yansheng Du, et al., published May 15, 2003, entitled “Use of tetracyclines as neuro-protective agents and for the treatment of Parkinson's disease and related disorders,” discloses the use of a tetracycline, preferably minocycline, for manufacture of a pharmaceutical composition for treatment or prevention of a disorder selected from Parkinson's disease and related disorders, such as Alzheimer's disease. The mechanism of action of the desired protection is not discussed, nor are minocycline alternatives.
This is in contrast to the present invention, described below, which, inter alia, does not use minocycline or other known tetracycline derivatives, and, further, uses compounds which do not have antibiotic activity.